PPARγ as an Integrator of Developmental Lung Reprogramming by Early-Life Per- and Polyfluoroalkyl Substances (PFAS)...

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants increasingly detected in maternal serum, breast milk, drinking water, and indoor environments, raising concern for fetal and early postnatal exposure during critical periods of lung development. Although epidemiologic and experimental studies link early-life PFAS exposure with altered immune function, impaired lung maturation, and later respiratory vulnerability, the molecular pathways underlying these effects remain incompletely defined. In this mini-review, we propose peroxisome proliferator-activated receptor gamma (PPARγ) as a central integrator of developmental lung reprogramming by PFAS. PPARγ regulates key processes required for normal alveolar maturation, including epithelial-mesenchymal interactions, lipofibroblast differentiation, epithelial barrier integrity, macrophage polarization, and inflammatory homeostasis. Recent evidence, including our own, indicates that in the developing lung PFAS exposure is associated with suppression of pulmonary PPARγ expression and signaling while relatively sparing PPARα, and that pharmacologic modulation of PPARγ significantly alters PFAS-induced epithelial inflammatory responses. We discuss how PFAS-mediated disruption of PPARγ signaling, potentially through direct pulmonary effects as well as indirect placental and endocrine mechanisms, may link structural and immune reprogramming by altering lipofibroblast identity, impairing alveolar maturation, altering epithelial permeability, and promoting macrophage programs that amplify later allergic susceptibility. We further highlight developmental timing, exposure mixture, and sex-divergent outcomes as emerging modifiers of this pathway. Defining how PFAS perturbs PPARγ-dependent developmental programs may provide a practical mechanistic framework for understanding environmentally programmed respiratory disease.